title: Effects of amphotericin B on Aspergillus flavus clinical isolates with variable susceptibilities to the polyene in an experimental model of systemic aspergillosis.
abstract: OBJECTIVE
  The aim of the present study was to evaluate the effects of amphotericin B (AMB) on clinical isolates of Aspergillus flavus.
  
  
  METHODS
  MICs of both standard AMB and liposomal AMB (L-AMB) were determined using a broth dilution method for seven isolates of A. flavus. AMB MICs were also determined using the Etest. The activity of the polyene was then investigated in a murine model of systemic aspergillosis in which animals were infected intravenously, treated intravenously with several doses of the polyene (1-10 mg/kg/day) and observed for survival.
  
  
  RESULTS
  Broth dilution AMB, broth dilution L-AMB and Etest AMB MICs ranged from 0.5 to 2.0 mg/L, 0.06 to >16 mg/L and 1.0 to >32 mg/L, respectively. There were two isolates for which all doses were effective at prolonging the survival. Their AMB MICs were ≤1.0 mg/L, regardless of the method/drug formulation utilized for testing. There were four isolates for which no regimen was effective. Their broth dilution AMB, broth dilution L-AMB and Etest AMB MICs ranged from 1.0 to 2.0 mg/L, 0.06 to >16 mg/L and 2.0 to >32 mg/L, respectively. There was one isolate for which only L-AMB given at 10 mg/kg/day was effective; broth dilution MICs of AMB and L-AMB were 0.5 mg/L, while the Etest MIC of AMB was 2.0 mg/L.
  
  
  CONCLUSIONS
  Our data indicate that not all isolates of A. flavus should be considered resistant to AMB. The Etest represented the in vitro method that best correlated with the experimental infection. Finally, a clinical isolate showing an MIC ≥2.0 mg/L may be reasonably considered resistant in vivo to any dose/formulation of the polyene.
authors.affiliation: Department of Biomedical Sciences and Public Health, Infectious Diseases Clinic, Università Politecnica delle Marche, Ancona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Barchiesi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Spreghini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Sanguinetti
authors.forename: Daniele
authors.initials: D
authors.lastname: Giannini
authors.forename: Esther
authors.initials: E
authors.lastname: Manso
authors.forename: Pamela
authors.initials: P
authors.lastname: Castelli
authors.forename: Corrado
authors.initials: C
authors.lastname: Girmenia
mesh_terms: D061605:Administration, Intravenous; D000666:Amphotericin B / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001228:Aspergillosis / Q000382:microbiology*; D001231:Aspergillus flavus / Q000187:drug effects* / Q000302:isolation & purification; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D005260:Female; D051379:Mice; D008826:Microbial Sensitivity Tests; D011090:Polyenes / Q000627:therapeutic use*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000935:Antifungal Agents; D011090:Polyenes; D000666:Amphotericin B
keywords: antifungal resistance; antifungal susceptibility testing; in vitro–in vivo correlation